The present invention relates to acylates for treatment of a disease or condition related to a neurotransmitter defect or deficiency, or to another central or peripheral. nervous system defect or deficiency.
As detailed, for example, in U.S. Pat. No. 4,826,877 (Stewart et al.) and U.S. Pat. No. 4,868,212 (Horrobin), the essential fatty acids consist of the n-3 series derived from and including xcex1-linolenic acid and the n-6 series derived from and including linoleic acid; since neither xcex1-linolenic acid nor linoleic acid are manufactured in the body, they must be provided by food. The n-3 series thus includes xcex1-linolenic, xcex94-6,9,12,15-octadecatetraenoic, xcex94-8,11,14,17-eicosatetraenoic, xcex94-5,8,11,14,17-eicosapentaenoic, xcex94-7,10,13,16,19-docosapentaenoic and xcex94-4,7,10,13,16,19-docosahexaenoic acids, and the n-6 series thus includes linoleic, xcex94-6,9,12-octadecatrienoic (xcex3-linolenic), xcex94-8,11,14,-eicosatrienoic (dihomo-xcex3-linolenic), xcex94-5,8,11,14-eicosatetraenoic (arachidonic), xcex94-7,10,13,16-docosatetraenoic (adrenic) and xcex94-4,7,10,13,16-docosapentaenoic acids. The term xe2x80x9cessential fatty acidsxe2x80x9d in the present specification and claims means all twelve of the above-mentioned fatty acids.
In U.S. Pat. No. 4,826,877, there is described use of the essential fatty acids for the prevention or treatment of diabetic neuropathy and other long term complications of diabetes mellitus. In U.S. Pat. No. 4,868,212, such acids are used in treatment of atopic disorders, while in U.S. Pat. No. 5,591,446 (Melnik et al.), xcex3-linolenic and/or dihomo-xcex3-linolenic acids are used for atopy prophylaxis. In U.S. Pat. No. 4,497,827 (Nelson), arachidonic acid analogues are utilized as anti-inflammatory, antiallergenic and antibrochoconstriction agents. In U.S. Pat. No. 3,995,059 (Fukumaru), N-(xcex1-alkyl) benzylamides of C13-C25 aliphatic carboxylic acids are used for lowering elevated levels of cholesterol in the blood.
In U.S. Pat. Nos. 5,599,840, 5,468,776, 5,416,114, 5,288,755, 5,120,763 and 4,851,431, to Yehuda, S., there are described compositions which comprise a combination of xcex1-linolenic acid and linoleic acid, within a range of strictly defined proportions, stated to be useful in enhancing memory, producing analgesia, regulating sleep, inhibiting senility symptoms, and in treating Alzheimer""s disease and related dementia, and epilepsy. In International Patent Application No. PCT/IL97/00366, published May 28, 1998 as WO 98/21949, the same inventor described the application of essentially the same combination of acids, for the treatment of multiple sclerosis. By contrast, use of mixtures of xcex1-linolenic acid and linoleic acid in proportions outside of the specified range, or (as is implicit from the U.S. patents and explicit in WO 98/21949), each acid or xcex3-linolenic acid taken separately, or substituting xcex3-linolenic acid for xcex1-linolenic acid in a pharmacologically active mixture with linoleic acid, did not afford any significant pharmacological activity.
The contents of the U.S. Patents referred to in the present application, and of WO 98/21949, are incorporated herein by reference.
To the best of the present inventor""s knowledge, it has been neither disclosed nor suggested in the prior art, to utilize acylates derived from essential fatty acids, for treatment of a disease or condition related to a neurotransmitter defect or deficiency, or to another central or peripheral nervous system defect or deficiency. From another aspect, it does not appear to have been previously disclosed or suggested in the prior art, that essential fatty acids, by forming covalent bonds with naturally occurring xcex1-aminocarboxylic acids, neurotransmitters other than such acids, or central or peripheral nervous system pharmacologically active compounds, would thereby have the ability to transport such substances, in the form of the resultant acylates, across the blood-brain barrier.
Although a vast number of drugs are known to medicine, many do not realize their full potential because of the problem of applying them at an internal body site (such as appropriate receptors), where they would be most efficacious. Another aspect of this problem is the necessity to administer a relatively large amount of an expensive drug, in order that a very small fraction will reach the appropriate body site and exert a pharmacological effect. The usual procedures for drug administration are consequently uneconomical and also frequently produce undesired side-effects.
It is an important object of the present invention to advance the science of pharmacology in order to avoid so far as possible the problems set forth in the preceding paragraph. Other objects of the invention will appear from the description which follows.
In one aspect, the present invention provides an acylate which is the reaction product of: (a) a substance which is selected from the group consisting of naturally occurring xcex1-aminocarboxylic acids, neurotransmitters other than such acids, and central nervous system pharmacologically active compounds, and containing a functional group including an acylatable hydrogen atom, or a reactive derivative thereof; and (b) an essential fatty acid or a reactive derivative thereof.
In another aspect, the invention provides use of at least one acylate as defined in the preceding paragraph, in the manufacture of a medicament for treatment of a disease or condition related to a neurotransmitter defect or deficiency, or to another central or peripheral nervous system defect or deficiency.
In still another aspect, the invention provides a method for treatment of a disease or condition related to a neurotransmitter defect or deficiency, or to another central or peripheral nervous system defect or deficiency, wherein there is administered to a human or non-human mammal an effective amount of at least one acylate as defined in the last paragraph but one.
In yet a further aspect, the present invention also provides a pharmaceutical formulation which comprises at least one acylate of the invention, together with at least one carrier, diluent or adjuvant.
For the avoidance of doubt, it is to be noted that the preparation of the acylates of the present invention involves the formation of a covalent bond or bonds between a substance defined under (a), above, and one or more molecular proportions of component (b) as defined above. The acylates may be N-acylates, O-acylates or S-acylates, or a mixture of more than one of these types of acylate.
Included in the compounds of the present invention are functional derivatives of the present acylates, and in particular of such acylates which contain residual amino, carboxyl and/or hydroxyl groups. The nature and range of such functional groups will be well known to persons of the art. Presently preferred functional derivatives of acylates containing one or more carboxylic groups are esters thereof with alcohols containing 1-4 carbon atoms. The functional derivatives appear to have similar biological activity to the non-functionalized acylates.
While the scope of the present invention is deemed not to be restricted by any theory, it is nevertheless presently believed that enzymes associated with relevant receptors will split the covalent bond between moieties (a) and (b), whereby component (a) exhibits its pharmacological activity at the site in question while the essential fatty acidxe2x80x94component (b)xe2x80x94is absorbed in the neuronal membrane.
The acylates of the present invention, which by way of non-limiting exemplification may result from acylation with formation of a xe2x80x94COxe2x80x94Oxe2x80x94, xe2x80x94COxe2x80x94Sxe2x80x94 or xe2x80x94COxe2x80x94NR1R2 moiety (where each of R1 and R2 is independently selected from a hydrogen atom or an optionally substituted hydrocarbyl group and NR1R2 may also constitute a heterocyclic ring), may be prepared by any of the appropriate methods known to the organic chemist, and thus the manner of their preparation does not constitute, per se, a part of the present invention. Where, in the standard methods of reaction for preparing e.g., the amides, esters or thioesters which may be acylates according to the present invention, reactant (a) contains an atom or substituent which interferes with such reaction, then such interfering atom or substituent may be blocked or protected in a manner known to persons in the art.
Although the present acylates will frequently be pro-drugs, that is, substances which when administered in the animal or human body release at the desired site a pharmacologically active entity, nevertheless, this in the alternative or additionally, the acylates may have pharmacological activity in their own right. Further, the acylates include substances in which component (a) is not itself pharmacologically active at the target site, but when released metabolizes to a substance having desired pharmacological activity.
Group (a) substances include naturally occurring (x-aminocarboxylic acids, which are of course xe2x80x9cbuilding blocksxe2x80x9d in the formation of proteins which perform important functions in the animal and human body, and at least some of which acids functional also as neurotransmitters. Exemplary amino acids are xcex1-aminocarboxylic acids and are selected from alanine, arginine, asparagine, aspartic acid, xcex2-carboxyaspartic acid, xcex3-carboxyglutamic acid, cysteine, cystine, glutamine, glutamic acid, glycine, histidine, homoserine, hydroxylysine, hydroxyproline, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine.
Two amino acids of particular importance, tyrosine and tryptophan, are not formed in the body but must be ingested in food. Tyrosine is metabolized successively to dopa, dopamine, norepinephrine and epinephrine (Scheme A, below), while tryptophan is metabolized first to 5-hydroxytryptophan and thus to 5-hydroxytryptamine (Scheme B, below). 
Group (a) substances further include other neurotransmitters, e.g., xcex3-aminobutyric acid (GABA), Dopamine, Epinephrine, Norepinephrine and 5-hydroxytryptamine. It will be apparent that the amino acids tyrosine and tryptophan thus perform, in the present context, the invaluable function of forming neurotransmitters in the body.
While Parkinson""s Disease is related to a deficiency of the central neurotransmitter dopamine, this cannot be administered to patients because is cannot pass the blood-brain barrier. The conventional solution to this problem is the administration of Levodopa; however, this always causes undesirable side-effects, to a greater or lesser extent. Thus, in accordance with an embodiment of the present invention, there is provided a method for the treatment of Parkinson""s Disease which comprises treating a patient with an effective amount of at least one compound selected from N- and/or O-acylated derivatives of tyrosine, levodopa and dopamine, where the acyl group is that of an essential fatty acid, such as, e.g., xcex1- or xcex3-linolenoyl, linoleoyl or arachidonoyl.
Such derivatives constitute presently preferred acylates of the invention, as do also the N- and/or O-acylated derivatives of epinephrine and norepinephrine; the N-acylated derivatives of tryptophan; and the N- and/or O-acylated derivatives of 5-hydroxytryptophan and 5-hydroxytryptamine, in all of which the acyl group is that of an essential fatty acid, such as, e.g., xcex1- or xcex3-linolenoyl, linoleoyl or arachidonoyl.
It is believed to be a clear implication from the specific example set forth herein, that the acylates of the present invention (in relation to central neurotransmitters and the treatment of CNS-related conditions generally) are able to pass the blood-brain barrier, and it may be predicted with a reasonable degree of confidence that they would have the ability also to access appropriate receptors in relation to peripheral nervous system conditions.
By definition, substance (a) must contain a functional group including an acylatable hydrogen atom, or a reactive derivative thereof, in order that it may potentially be reacted with an essential fatty acid (or a reactive derivative thereof), so as to result in formation of a prodrug according to the present invention. The Table which follows shows, by way of non-limiting illustration only, substances (a), classified according to their pharmacological activity, and indicating the nature of the functional group (rather than the category of compound) containing the hydrogen atom substitutable by e.g., xcex1- or xcex3-linolenoyl, linoleoyl or arachidonoyl.
The acylates of the invention may be formulated with carriers, diluents and adjuvants as is well known in the pharmaceutical art and they may be administered in the usual modes, such as orally, parenterally, rectally of transdermally. Consequently, the present pharmaceutical formulations, except insofar as they contain the present novel and inventive acylates, are not otherwise to be regarded as innovative per se, and they may be manufactured and administered by known methods.